1. Field of the Inventive Concept(s)
The presently disclosed and claimed inventive concept(s) relates generally to peptide compositions, and in particular, but not by way of limitation, to Surfactant-A-protein peptide compositions and derivatives thereof, and methods of producing and using same.
2. Description of the Background Art
The pathogen-pattern recognition receptors (PPRRs) are important components of innate immunity that sense the pathogenic stimuli and regulate host immune responses (Pastva et al., 2007; Wright, 1997). Surfactant protein-A (SP-A) and Toll-like receptor-4 (TLR4) have been identified as important PPRRs (Barton, 2007; Brinker et al., 2003; Hoebe et al., 2006; Kawai and Akira, 2007; Kuroki et al., 2007; Miyake, 2007). TLR4 is expressed as a transmembrane receptor and is known as a “Signalling-PPRR” (Kawai and Akira, 2007). On the other hand, SP-A is synthesized by type II lung epithelial cells and secreted in the alveoli as a component of surfactant. SP-A is known as a “Secretory-PPRR” (Pastva et al., 2007). It has been demonstrated by the inventor and others that SP-A constitutes the majority of surfactant proteins (SPs) (Johansson and Curstedt, 1997) and plays a critical role in the clearance of pathogens and downregulation of the inflammatory response (see also, Awasthi, 2010). On the other hand, TLR4 recognizes pathogen or pathogen-derived ligands and endogenous stress proteins, and induces inflammatory and adaptive immune responses. In a number of diseases, including but not limited to lung inflammatory conditions, an exaggerated activation of TLR4 has been found associated with NF-κB and pro-inflammatory cytokine response (Guillot et al., 2004; He et al., 2009; Lv et al., 2009; Maes et al., 2006; Villar et al., 2010).
Published reports suggest that the bronchioalveolar lavage pools (extracellular pools) of SP-A are significantly reduced in lungs of infected patients and animal models (Alcorn et al., 2005; Awasthi et al., 1999; Awasthi et al., 2001; Awasthi et al., 2004; Chang et al., 2006; Kajikawa et al., 2005). In contrast, TLR4 expression is increased (Awasthi et al., 2008; Chang et al., 2006; Gagro et al., 2004; Kajikawa et al., 2005). The reduction in the amounts of SP-A, and simultaneous increase in TLR4 expression corroborates well with the clinical condition of patients having fulminant infection and inflammation, respectively. In these clinical scenarios, the introduction of SP-A should facilitate clearance of pathogens and attenuate inflammation. However, currently-available clinical surfactants (used for improving lung function and maturity in pre-term infants) do not contain SP-A or SP-D because it is difficult to mix large hydrophilic SP-A proteins with lipids. As with any large protein, rapid clearance of large proteins, degradation and a non-specific immune response have also hampered the development of clinical surfactant having SP-A.
Inflammatory Bowel Disease (IBD) causes chronic inflammation in the intestine and accounts for a huge economic cost associated with multiple clinic visits and hospitalizations. Therapeutic efficacy with currently recommended drugs has been limited because of toxic effects, nonspecific downregulation of overall immunity and increased risk of infection. Contemporary understanding suggests that activation of Toll-like receptor-4 (TLR4) and TLR4-nuclear factor (NF)-kappa B signaling in the gut causes an overproduction of inflammatory cytokines and trafficking of leukocytes, thus leading to uncontrolled intestinal inflammation. Moreover, persistent inflammation can lead to carcinogenesis. Thus, new therapies targeting TLR4 may be of clinical utility in these conditions.
Interestingly, recently published reports suggested that SP-A directly binds to TLR4 (Guillot et al., 2002; Yamada et al., 2006). However, the in vivo evidence of such an interaction has been lacking, and its functional relevance has not been fully elucidated.
Therefore, there is a need in the art for an understanding of the functional relationship of TLR4 and SP-A, as well as compositions that interact in and/or inhibit said interaction and thereby block TLR4 signaling. It is to said compositions, as well as methods of producing and using same, that the presently disclosed and claimed inventive concept(s) is directed.